This invention relates to compositions of an active agent and a .beta.-cyclodextrin derivative which are topically effective in treating eye conditions.
Glaucoma is a degenerative disease of the eye characterized by optic nerve loss, often in a characteristic nerve fiber bundle configuration. If untreated, glaucoma will eventually lead to blindness. More than 1% of Americans over the age of 40 suffer from this potentially blinding condition. Black Americans are 4 times more likely to suffer from glaucoma and 6-8 times more likely to be blind from glaucoma than are white Americans. The most important risk factor for glaucomatous optic nerve damage is elevated intraocular pressure (IOP). Although there is a real, albeit low, risk of glaucoma in persons with normal IOP (i.e., 16 mm Hg), the glaucoma risk in persons with even mild elevation of IOP (i.e., &gt;22 mm Hg) is elevated 10-fold. When IOP is over 28 mm Hg, the glaucoma risk is approximately 40-fold higher than when IOP is normal.
Four major classes of pharmacologic agents are currently employed to lower IOP on a chronic basis: .beta.-adrenergic blockers, miotics, .alpha.-adrenergic agonists, and carbonic anhydrase inhibitors. However, none of the currently available pharmacologic agents is entirely satisfactory. At least 10% of glaucoma sufferers require laser and/or incisional surgery, in addition to medical therapy, to achieve adequate control of IOP. Even when pharmacologic control is possible, the side effects of current agents, combined with poor patient compliance, limit their effectiveness.
Miotic agents, of which pilocarpine is the most frequently used, lower IOP by increasing aqueous outflow through the trabecular meshwork of the eye. Although their topical use is associated with minimal systemic side effects, they frequently cause objectionable ocular and periocular effects. Miotic agents generally cause pupillary constriction, which severely diminishes night vision, and also induce myopia (near-sightedness). Often patients will complain of an objectionable headache or browache associated with topical administration of these compounds.
.beta.-adrenergic blocking agents, of which timolol is the most frequently used, lower IOP by decreasing aqueous secretion. At least five different .beta.-adrenergic blockers are in topical use in the United States with comparable effectiveness. A reduction of up to 25% in IOP can generally be expected when starting a patient on therapy with these agents. Although the .beta.-adrenergic blockers have few ophthalmologic side effects, their systemic side effects can be severe, and occasionally fatal. Topically administered ophthalmologic .beta.-adrenergic blockers can have the same spectrum of systemic side effects as those administered orally or parenterally. Presumably this is a function of drainage through the nasolacrimal duct with absorption across the nasal mucosa. Side effects include heart failure, bradycardia, bronchospasm, dizziness, syncope, depression, dementia, and impotence. At least 10% of patients begun on topical .beta.-adrenergic blockers experience one or more of these symptoms, and there is a widely held belief that greater prevalence of these side effects goes unrecognized.
The .alpha.-adrenergic agonist class of compounds is best exemplified by epinephrine and related compounds. While they are used topically in the form of eye drops, in general, they exert less of a pressure-lowering effect than other classes of agents. Patients frequently develop sensitivity to epinephrine and dipiviphrine when used for a year or longer.
Although considerable effort has been directed towards developing topically active carbonic anhydrase inhibitors, they are currently available only for systemic use. While extremely effective at lowering pressure, they often cause numbness and tingling, gastrointestinal upset, depression, lethargy, loss of appetite, and general malaise. These, in addition to the occasional severe systemic reaction, such as aplastic anemia, are so common that many physicians are reluctant to routinely prescribe carbonic anhydrase inhibitors for long-term use.
While investigators have long realized the benefits that would accompany topical administration of carbonic anhydrase inhibitors, the selection of the proper coformulation entity has long eluded them. Most reports in the literature indicate that carbonic anhydrase inhibitors are inactive topically because they cannot cross the cornea. See, for example, U.S. Pat. Nos. 4,888,168 (e.g., column 1, lines 30-36), and 4,619,939 (e.g., column 3, lines 50-53). In some cases, even direct injection of carbonic anhydrase inhibitors into the anterior chamber has been shown to have no pressure lowering effect.
Because carbonic anhydrase inhibitors have a profound effect in altering basic metabolism, the avoidance of a systemic route serves to diminish, if not entirely eliminate, those side effects caused by metabolic acidosis such as hypokalemia, numbness, tingling, general malaise, etc.
Silvistrini, "Effects of Topically Instilled Drugs on Intraocular Pressure in Rabbits", Arzeim.-Forsch. (Drug Res.) 25, Nr. 5 (1975), teaches that the disodium salts of acetazolamide can be used to lower the intraocular pressure of the normal rabbit eye. Silvestrini and subsequent investigators fail to confront the problem associated with the high pH of disodium salt solutions and the significant probability of severe irritation. Attempts to buffer the solutions to a near-physiologic pH generally lead to precipitation of the metal salt.
On the other hand, there is a large body of disclosure supporting the use of cyclodextrin compounds, especially hydroxypropyl-.beta.-cyclodextrin, as excipients for solubilizing non-polar molecules, including a variety of pharmaceutical agents. Hydroxypropyl-.beta.-cyclodextrin (HPBCD) and its preparation by propylene oxide addition to .beta.-cyclodextrin was described in Gramera et al., U.S. Pat. No. 3,459,791. Gramera et al. specifically teach the use of HPBCD to alter the solubility of desirable guest molecules, such as flavoring agents or pharmaceutical agents (column 6, lines 34-37).
Much more recently, Pitha, U.S. Pat. No. 4,596,795, disclosed that the amorphous nature of particular .beta.-cyclodextrin derivatives contributed to the solubilizing effect. Likewise, Muller et al., WO85/02767, disclosed that hydroxyalkyl ethers of .beta.-cyclodextrin are useful for dissolving sparingly water-soluble drugs and for increasing their bioavailability. All examples of the .beta.-cyclodextrin composition in Muller et al. were low viscosity aqueous solutions of between 5% and 7.5% of the .beta.-cyclodextrin derivative combined with 1% or less of the active agent. Muller et al. specifically teaches (Example 7) that when a 0.75% solution of lidocaine, a highly water-soluble compound is constituted in a 5% or 7.5% solution of hydroxypropyl-.beta.-cyclodextrin, there is an increase in bioavailability, as measured by duration of anesthetic effect.
Jansen et al., Chemical Abstracts, CA115(2):15428n, disclose the potential use of .beta.-cyclodextrin derivatives in ophthalmic preparations. Although they found that dimethyl-.beta.-cyclodextrin is toxic to the rabbit corneal epithelium, 12.5% HPBCD was tolerated by the cornea when applied topically. However, when the effect of .beta.-cyclodextrin on the bioavailability of topically administered carbonic anhydrase inhibitor, L-671152, was studied, Grove et al., Chemical Abstracts, CA116:27958u, showed that .beta.-cyclodextrin at either 3% or 1.5% reduced ocular bioavailability to about 50% as compared to when the inhibitor was administered alone.